Biological membranes are dynamic and complex assemblies of lipids and proteins. Eukaryotic lipidomes encompass hundreds of distinct lipid species and we have only begun to understand their role and function. This review focuses on recent advances in the field of lipid sensors and discusses methodical approaches to identify and characterize putative sensor domains. We elaborate on the role of integral and conditionally membrane-associated sensor proteins, their molecular mechanisms, and identify open questions in the emerging field of membrane homeostasis.